Synthesis and biological evaluation of C-2 halogenated analogs of salvinorin A

✍ Scribed by David Y.W. Lee; Lu Yang; Wei Xu; Gang Deng; Lin Guo; Lee-Yuan Liu-Chen

• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 358 KB
• Volume: 20
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.08.001

✦ Synopsis

Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective κ opioid receptor (KOPR) agonist. Based on the SAR, its C-2 position is one of the key binding sites and has very little space tolerance (3-4 carbons atoms) and limited to only lipophilic groups. In our attempt to prepare PET brain imaging agent for mapping KOPR, a series of C-2 halogenated analogs have been synthesized and screened for binding affinity at κ (KOPR), μ (MOPR), and δ (DOPR). These C-2 halogenated analogs with sequential changes of atomic radius and electron density serve as excellent molecular probes for further investigating the binding pocket at C-2, particularly on the effects of α verses β configuration at C-2 position. The results of KOPR binding and functional studies reveal β isomer in general binds better than α isomer with the exception of iodinated analogs and none of the C-2 halogenated analogs shows any improvement of KOPR binding affinity. Interestingly, functional assay has characterized that 6b is a partial agonist with E(max) of 46% of the kappa receptor full agonist U50,488H at 250 nM (K(i)). We have also observed that the affinity to the kappa receptor increases with atomic radius (I>Br>Cl>F) which is in good agreement with halogen bonding interactions reported in the literature.